Our published preliminary studies indicate that pulmonary hypertension occurs in nearly one-third of adults with sickle cell disease, that it is associated with increased mortality although pulmonary artery pressures are lower than in patients with primary pulmonary hypertension, and that chronic hemolysis with nitric oxide scavenging may be a part of the pathogenesis. The present proposal is based on three postulates. First, the problem of sickle cell-associated pulmonary hypertension may begin during childhood and adolescence. A retrospective analysis and our own preliminary data suggest pulmonary hypertension prevalence of up to 25% in adolescents. Second, the pathogenesis of sickle cell-associated pulmonary hypertension may not only include the effects of chronic hemolysis, but also the consequences of chronic hypoxia related to severe anemia and repeated vasoocclusive episodes. Pulmonary hypertension is a recognized complication of conditions marked by chronic hypoxia, and we have recently found evidence that pulmonary hypertension complicates Chuvash polycythemia, a congenital disorder of oxygen sensing in which the hypoxic response is constitutively up regulated in the absence of hypoxia and in which high hemoglobin concentrations would promote nitric oxide scavenging. Third, the pathophysiology of sickle cell-associated pulmonary hypertension may be elucidated by comparing components of the hypoxic response in patients with sickle cell disease and Chuvash polycythemia according to the presence or absence of pulmonary hypertenson. Both sickle cell disease and Chuvash polycythemia may be characterized by nitric oxide scavenging and upregulated hypoxia inducible factor, leading to stimulation of pulmonary vascular proliferative pathways that eventuate in pulmonary hypertension. Comparing specific responses in both conditions may identify shared pathways that have a central role in sickle cell-related pulmonary hypertenison. This is an observational study of pulmonary hypertension in a) children and adolescents with sickle cell disease and b) children, adolescents and adults with sickle cell disease or Chuvash polycythemia. In both a and b there are two arms- one that contains patients and one that contains controls from the background population. The total number of subjects enrolled is now 660. At this point of interim analysis, 310 children and adolescents with sickle cell disease in steady state was conducted. Hemolysis and hemoglobin had no significant correlation with the number of severe pain episodes, acute chest syndrome and priapism. The hemolytic index correlated with history of stroke (r=0.19, p=0/026), white blood cell count (r=0.22, p<0.001), tricuspid regurgitation velocity (r=0.25, p<0.001), left ventricular mass index (r=0.33, p<0.001) left ventricular internal diastolic z score (r=0.30, p<0.001) and hemoglobin oxygen desaturation (r=0.30, p<0.001) but not independently with platelet count and creatinine and six-minute walk. These observations support the hypothesis that a hemolytic vasculopathy independent of the degree of anemia contributes to the pathogenesis of stroke and pulmonary hypertension and to the development of increased systemic vascular resistance. They also raise the possibility that leukocytosis may in part serve as a predictor of poor outcome by its association with hemolysis. Therapeutic interventions that reduce the rate of hemolysis need to be studied for their potential benefit in decreasing the risk and severity of vasculopathy and the resulting organ damage. The NIH Clinical Center does not enroll subjects under this protocol, but provides laboratory support and data management.